Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


The Analysis of Denosumab Discontinuation and Associated Fracture Incidence in the FREEDOM Trial.

Brown1,  Jacques P., Jensen2,  Jens-Erik Beck, Recknor3,  Chris, Roux4,  Christian, Torring5,  Ove, Austin6,  Matt, Wang6,  Andrea

CHUQ-CHUL Research Centre, Laval University, Quebec City, QC
Hvidovre Hospital, Hvidovre, Denmark
United Osteoporosis Centers, Gainesville, GA
Paris Descartes University, Paris, France
Institution for Clinical Science and Education Södersjukhuset Karolinska Institutet, Stockholm, Sweden
Amgen Inc., Thousand Oaks, CA

Background/Purpose:

Denosumab, a reversible RANKL inhibitor, decreases osteoclast formation, function, and survival. In the pivotal phase 3 fracture trial, FREEDOM, denosumab 60 mg administered every 6 months decreased the risk for new vertebral, nonvertebral, and hip fractures over 3 years compared with placebo (Cummings NEJM 2009). Osteoporosis is a chronic disease, and continued treatment is required to provide anti-fracture efficacy. While cessation of denosumab treatment has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD) (Miller Bone 2008; Bone JCEM 2011), the effect on fracture risk is not as well characterized.

Methods:

To understand fracture incidence in an osteoporotic population after treatment cessation, we evaluated subjects in FREEDOM who discontinued treatment after receiving 2 to 5 doses of investigational product (IP), either denosumab or placebo, and continued study participation for >= 6 months since the last dose + 1-month study visit window (>= 7 months). The off-treatment observation period, which varies from subject to subject, began 7 months after the last dose of IP and lasted for approximately 6 to 24 months (for subjects who received 5 and 2 doses, respectively).

Table. Subject Characteristics at Treatment Discontinuation

 Placebo (N = 470)Denosumab (N = 327)
Number of doses received
  2114 (24)86 (26)
  3138 (29)99 (30)
  490 (19)68 (21)
  5128 (27)74 (23)
Fracture during treatment*90 (19)36 (11)
Significant BMD reduction† during treatment*80 (17)4 (1)
Treatment discontinuation due to requiring alternative therapy or disease progression116 (25)29 (9)
Started alternative therapy after last dose197 (42)90 (28)
Values are number (%) of subjects. N = number of subjects who discontinued treatment after receiving 2 to 5 doses of investigational product, either denosumab or placebo, and continued study participation for >= 7 months after the last dose.*Treatment period = first dose through last dose + 7 months.†Significant BMD reduction is defined as > 7% BMD reduction at the total hip within any 12-month period, >= 10% BMD reduction at total hip from baseline at any time point, or total hip BMD T-score < -4 at any time point.

Results:

This subgroup of 797 subjects (470 placebo, 327 denosumab) showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T-scores. During the treatment period, more subjects treated with placebo as compared with denosumab sustained a fracture and had significant decreases in BMD (Table). In addition, 42% of placebo-treated subjects vs 28% of denosumab-treated subjects initiated an alternative therapy after the last dose. After treatment discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject-years of 13.5 for placebo and 9.7 for denosumab (HR 0.82; 95% CI: 0.49, 1.38), adjusted for age and total hip BMD T-score at baseline. There was no apparent difference in fracture occurrence pattern between the treatment groups during the off-treatment period (Figure).

Conclusion:

We conclude from this analysis that there was not an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off-treatment period for up to 24 months.

To cite this abstract, please use the following information:
Brown, Jacques P., Jensen, Jens-Erik Beck, Recknor, Chris, Roux, Christian, Torring, Ove, Austin, Matt, et al; The Analysis of Denosumab Discontinuation and Associated Fracture Incidence in the FREEDOM Trial. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1098
DOI:

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